Summary Obesity perturbs metabolic homeostasis and has adverse effects on health. Obese patients have compromised immune function, increased risk for a hematological malignancy, and increased risk for non-relapse mortality following either autologous or allogeneic bone marrow transplantation. Abnormalities in hematopoiesis occur in obese individuals and may underlie their compromised immune and hematopoietic functions. We propose to investigate the molecular and cellular mechanisms that underlie deregulated hematopoiesis in obese patients. The overall hypothesis to be investigated is that obesity perturbs metabolic homeostasis in hematopoietic stem cells (HSCs), resulting in compromised HSC function and hematopoiesis. Supporting this hypothesis is our recent finding that a nutrient sensor, whose activity is inversely regulated by nutritional input, regulates mitochondrial metabolic homeostasis to promote stress resistance in HSCs and promotes their self-renewal and hematopoiesis under stress. We plan to greatly expand this initial finding to systemically investigate how obesity affects HSC function and hematopoiesis.